141 results on '"Lawley TD"'
Search Results
2. The gut microbial metabolic capacity of microbiome-humanized vs. wild type rodents reveals a likely dual role of intestinal bacteria in hepato-intestinal schistosomiasis.
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Downs, JA, Cortés, A, Martin, J, Rosa, BA, Stark, KA, Clare, S, McCarthy, C, Harcourt, K, Brandt, C, Tolley, C, Lawley, TD, Mitreva, M, Berriman, M, Rinaldi, G, Cantacessi, C, Downs, JA, Cortés, A, Martin, J, Rosa, BA, Stark, KA, Clare, S, McCarthy, C, Harcourt, K, Brandt, C, Tolley, C, Lawley, TD, Mitreva, M, Berriman, M, Rinaldi, G, and Cantacessi, C
- Abstract
Increasing evidence shows that the host gut microbiota might be involved in the immunological cascade that culminates with the formation of tissue granulomas underlying the pathophysiology of hepato-intestinal schistosomiasis. In this study, we investigated the impact of Schistosoma mansoni infection on the gut microbial composition and functional potential of both wild type and microbiome-humanized mice. In spite of substantial differences in microbiome composition at baseline, selected pathways were consistently affected by parasite infection. The gut microbiomes of infected mice of both lines displayed, amongst other features, enhanced capacity for tryptophan and butyrate production, which might be linked to the activation of mechanisms aimed to prevent excessive injuries caused by migrating parasite eggs. Complementing data from previous studies, our findings suggest that the host gut microbiome might play a dual role in the pathophysiology of schistosomiasis, where intestinal bacteria may contribute to egg-associated pathology while, in turn, protect the host from uncontrolled tissue damage.
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- 2022
3. A pilot study to understand feasibility and acceptability of stool and cord blood sample collection for a large-scale longitudinal birth cohort
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Bailey, SR, Townsend, CL, Dent, H, Mallet, C, Tsaliki, E, Riley, EM, Noursadeghi, M, Lawley, TD, Rodger, AJ, Brocklehurst, P, and Field, N
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Adult ,Pilot Projects ,lcsh:Gynecology and obstetrics ,Specimen Handling ,Feces ,Biological samples ,Acceptability ,Pregnancy ,Preoperative Care ,Infant faeces ,Humans ,Pregnancy, Prolonged ,Longitudinal Studies ,lcsh:RG1-991 ,Blood Specimen Collection ,Bioarchive ,Cesarean Section ,Cord blood ,Feasibility ,Patient Acceptance of Health Care ,Fetal Blood ,United Kingdom ,Large-scale birth cohorts ,Feasibility Studies ,Female ,Maternal Serum Screening Tests ,Research Article - Abstract
Background Few data are available to guide biological sample collection around the time of birth for large-scale birth cohorts. We are designing a large UK birth cohort to investigate the role of infection and the developing immune system in determining future health and disease. We undertook a pilot to develop methodology for the main study, gain practical experience of collecting samples, and understand the acceptability of sample collection to women in late pregnancy. Methods Between February–July 2014, we piloted the feasibility and acceptability of collecting maternal stool, baby stool and cord blood samples from participants recruited at prolonged pregnancy and planned pre-labour caesarean section clinics at University College London Hospital. Participating women were asked to complete acceptability questionnaires. Results Overall, 265 women were approached and 171 (65%) participated, with ≥1 sample collected from 113 women or their baby (66%). Women had a mean age of 34 years, were primarily of white ethnicity (130/166, 78%), and half were nulliparous (86/169, 51%). Women undergoing planned pre-labour caesarean section were more likely than those who delivered vaginally to provide ≥1 sample (98% vs 54%), but less likely to provide maternal stool (10% vs 43%). Pre-sample questionnaires were completed by 110/171 women (64%). Most women reported feeling comfortable with samples being collected from their baby (
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- 2017
4. Distinct microbial and immune niches of the human colon
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James, KR, primary, Gomes, T, additional, Elmentaite, R, additional, Kumar, N, additional, Gulliver, EL, additional, King, HW, additional, Stares, MD, additional, Bareham, BR, additional, Ferdinand, JR, additional, Petrova, VN, additional, Polanski, K, additional, Forster, SC, additional, Jarvis, LB, additional, Suchanek, O, additional, Howlett, S, additional, James, LK, additional, Jones, JL, additional, Meyer, KB, additional, Clatworthy, MR, additional, Saeb-Parsy, K, additional, Lawley, TD, additional, and Teichmann, SA, additional
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- 2019
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5. Interleukin-22 promotes phagolysosomal fusion to induce protection against Salmonella enterica Typhimurium in human epithelial cells
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Forbester, JL, Lees, EA, Goulding, D, Forrest, S, Yeung, A, Speak, A, Clare, S, Coomber, EL, Mukhopadhyay, S, Kraiczy, J, Schreiber, F, Lawley, TD, Hancock, REW, Uhlig, HH, Zilbauer, M, Powrie, F, Dougan, G, Forbester, JL, Lees, EA, Goulding, D, Forrest, S, Yeung, A, Speak, A, Clare, S, Coomber, EL, Mukhopadhyay, S, Kraiczy, J, Schreiber, F, Lawley, TD, Hancock, REW, Uhlig, HH, Zilbauer, M, Powrie, F, and Dougan, G
- Abstract
Intestinal epithelial cells (IECs) play a key role in regulating immune responses and controlling infection. However, the direct role of IECs in restricting pathogens remains incompletely understood. Here, we provide evidence that IL-22 primed intestinal organoids derived from healthy human induced pluripotent stem cells (hIPSCs) to restrict Salmonella enterica serovar Typhimurium SL1344 infection. A combination of transcriptomics, bacterial invasion assays, and imaging suggests that IL-22-induced antimicrobial activity is driven by increased phagolysosomal fusion in IL-22-pretreated cells. The antimicrobial phenotype was absent in hIPSCs derived from a patient harboring a homozygous mutation in the IL10RB gene that inactivates the IL-22 receptor but was restored by genetically complementing the IL10RB deficiency. This study highlights a mechanism through which the IL-22 pathway facilitates the human intestinal epithelium to control microbial infection.
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- 2018
6. Genome-Based Infection Tracking Reveals Dynamics of Clostridium difficile Transmission and Disease Recurrence
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Kumar, N, Miyajima, F, He, M, Roberts, P, Swale, A, Ellison, L, Pickard, D, Smith, G, Molyneux, R, Dougan, G, Parkhill, J, Wren, BW, Parry, CM, Pirmohamed, M, Lawley, TD, Kumar, N, Miyajima, F, He, M, Roberts, P, Swale, A, Ellison, L, Pickard, D, Smith, G, Molyneux, R, Dougan, G, Parkhill, J, Wren, BW, Parry, CM, Pirmohamed, M, and Lawley, TD
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BACKGROUND: Accurate tracking of Clostridium difficile transmission within healthcare settings is key to its containment but is hindered by the lack of discriminatory power of standard genotyping methods. We describe a whole-genome phylogenetic-based method to track the transmission of individual clones in infected hospital patients from the epidemic C. difficile 027/ST1 lineage, and to distinguish between the 2 causes of recurrent disease, relapse (same strain), or reinfection (different strain). METHODS: We monitored patients with C. difficile infection in a UK hospital over a 2-year period. We performed whole-genome sequencing and phylogenetic analysis of 108 strains isolated from symptomatic patients. High-resolution phylogeny was integrated with in-hospital transfers and contact data to create an infection network linking individual patients and specific hospital wards. RESULTS: Epidemic C. difficile 027/ST1 caused the majority of infections during our sampling period. Integration of whole-genome single nucleotide polymorphism (SNP) phylogenetic analysis, which accurately discriminated between 27 distinct SNP genotypes, with patient movement and contact data identified 32 plausible transmission events, including ward-based contamination (66%) or direct donor-recipient contact (34%). Highly contagious donors were identified who contributed to the persistence of clones within distinct hospital wards and the spread of clones between wards, especially in areas of intense turnover. Recurrent cases were identified between 4 and 26 weeks, highlighting the limitation of the standard <8-week cutoff used for patient diagnosis and management. CONCLUSIONS: Genome-based infection tracking to monitor the persistence and spread of C. difficile within healthcare facilities could inform infection control and patient management.
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- 2016
7. Defining the Roles of TcdA and TcdB in Localized Gastrointestinal Disease, Systemic Organ Damage, and the Host Response during Clostridium difficile Infections
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Ballard, J, Collier, RJ, Carter, GP, Chakravorty, A, Tu, APN, Mileto, S, Schreiber, F, Li, L, Howarth, P, Clare, S, Cunningham, B, Sambol, SP, Cheknis, A, Figueroa, I, Johnson, S, Gerding, D, Rood, JI, Dougan, G, Lawley, TD, Lyras, D, Ballard, J, Collier, RJ, Carter, GP, Chakravorty, A, Tu, APN, Mileto, S, Schreiber, F, Li, L, Howarth, P, Clare, S, Cunningham, B, Sambol, SP, Cheknis, A, Figueroa, I, Johnson, S, Gerding, D, Rood, JI, Dougan, G, Lawley, TD, and Lyras, D
- Abstract
UNLABELLED: Clostridium difficile is a leading cause of antibiotic-associated diarrhea, a significant animal pathogen, and a worldwide public health burden. Most disease-causing strains secrete two exotoxins, TcdA and TcdB, which are considered to be the primary virulence factors. Understanding the role that these toxins play in disease is essential for the rational design of urgently needed new therapeutics. However, their relative contributions to disease remain contentious. Using three different animal models, we show that TcdA(+) TcdB(-) mutants are attenuated in virulence in comparison to the wild-type (TcdA(+) TcdB(+)) strain, whereas TcdA(-) TcdB(+) mutants are fully virulent. We also show for the first time that TcdB alone is associated with both severe localized intestinal damage and systemic organ damage, suggesting that this toxin might be responsible for the onset of multiple organ dysfunction syndrome (MODS), a poorly characterized but often fatal complication of C. difficile infection (CDI). Finally, we show that TcdB is the primary factor responsible for inducing the in vivo host innate immune and inflammatory responses. Surprisingly, the animal infection model used was found to profoundly influence disease outcomes, a finding which has important ramifications for the validation of new therapeutics and future disease pathogenesis studies. Overall, our results show unequivocally that TcdB is the major virulence factor of C. difficile and provide new insights into the host response to C. difficile during infection. The results also highlight the critical nature of using appropriate and, when possible, multiple animal infection models when studying bacterial virulence mechanisms. IMPORTANCE: Clostridium difficile is a leading cause of antibiotic-associated diarrhea and an important hospital pathogen. TcdA and TcdB are thought to be the primary virulence factors responsible for disease symptoms of C. difficile infections (CDI). However, the individual con
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- 2015
8. Neutrophils Recruited by IL-22 in Peripheral Tissues Function as TRAIL-Dependent Antiviral Effectors against MCMV
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Stacey, MA, Marsden, M, Pham, TAN, Clare, S, Dolton, G, Stack, G, Jones, E, Klenerman, P, Gallimore, AM, Taylor, PR, Snelgrove, RJ, Lawley, TD, Dougan, G, Benedict, CA, Jones, SA, Wilkinson, GWG, Humphreys, IR, Stacey, MA, Marsden, M, Pham, TAN, Clare, S, Dolton, G, Stack, G, Jones, E, Klenerman, P, Gallimore, AM, Taylor, PR, Snelgrove, RJ, Lawley, TD, Dougan, G, Benedict, CA, Jones, SA, Wilkinson, GWG, and Humphreys, IR
- Abstract
During primary infection, murine cytomegalovirus (MCMV) spreads systemically, resulting in virus replication and pathology in multiple organs. This disseminated infection is ultimately controlled, but the underlying immune defense mechanisms are unclear. Investigating the role of the cytokine IL-22 in MCMV infection, we discovered an unanticipated function for neutrophils as potent antiviral effector cells that restrict viral replication and associated pathogenesis in peripheral organs. NK-, NKT-, and T cell-secreted IL-22 orchestrated antiviral neutrophil-mediated responses via induction in stromal nonhematopoietic tissue of the neutrophil-recruiting chemokine CXCL1. The antiviral effector properties of infiltrating neutrophils were directly linked to the expression of TNF-related apoptosis-inducing ligand (TRAIL). Our data identify a role for neutrophils in antiviral defense, and establish a functional link between IL-22 and the control of antiviral neutrophil responses that prevents pathogenic herpesvirus infection in peripheral organs.
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- 2014
9. Epithelial IL-22RA1-Mediated Fucosylation Promotes Intestinal Colonization Resistance to an Opportunistic Pathogen
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Pham, TAN, Clare, S, Goulding, D, Arasteh, JM, Stares, MD, Browne, HP, Keane, JA, Page, AJ, Kumasaka, N, Kane, L, Mottram, L, Harcourt, K, Hale, C, Arends, MJ, Gaffney, DJ, Dougan, G, Lawley, TD, Pham, TAN, Clare, S, Goulding, D, Arasteh, JM, Stares, MD, Browne, HP, Keane, JA, Page, AJ, Kumasaka, N, Kane, L, Mottram, L, Harcourt, K, Hale, C, Arends, MJ, Gaffney, DJ, Dougan, G, and Lawley, TD
- Abstract
Our intestinal microbiota harbors a diverse microbial community, often containing opportunistic bacteria with virulence potential. However, mutualistic host-microbial interactions prevent disease by opportunistic pathogens through poorly understood mechanisms. We show that the epithelial interleukin-22 receptor IL-22RA1 protects against lethal Citrobacter rodentium infection and chemical-induced colitis by promoting colonization resistance against an intestinal opportunistic bacterium, Enterococcus faecalis. Susceptibility of Il22ra1(-/-) mice to C. rodentium was associated with preferential expansion and epithelial translocation of pathogenic E. faecalis during severe microbial dysbiosis and was ameloriated with antibiotics active against E. faecalis. RNA sequencing analyses of primary colonic organoids showed that IL-22RA1 signaling promotes intestinal fucosylation via induction of the fucosyltransferase Fut2. Additionally, administration of fucosylated oligosaccharides to C. rodentium-challenged Il22ra1(-/-) mice attenuated infection and promoted E. faecalis colonization resistance by restoring the diversity of anaerobic commensal symbionts. These results support a model whereby IL-22RA1 enhances host-microbiota mutualism to limit detrimental overcolonization by opportunistic pathogens.
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- 2014
10. Functional genomics reveals that Clostridium difficile Spo0A coordinates sporulation, virulence and metabolism
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Pettit, LJ, Browne, HP, Yu, L, Smits, WK, Fagan, RP, Barquist, L, Martin, MJ, Goulding, D, Duncan, SH, Flint, HJ, Dougan, G, Choudhary, JS, Lawley, TD, Pettit, LJ, Browne, HP, Yu, L, Smits, WK, Fagan, RP, Barquist, L, Martin, MJ, Goulding, D, Duncan, SH, Flint, HJ, Dougan, G, Choudhary, JS, and Lawley, TD
- Abstract
BACKGROUND: Clostridium difficile is an anaerobic, Gram-positive bacterium that can reside as a commensal within the intestinal microbiota of healthy individuals or cause life-threatening antibiotic-associated diarrhea in immunocompromised hosts. C. difficile can also form highly resistant spores that are excreted facilitating host-to-host transmission. The C. difficile spo0A gene encodes a highly conserved transcriptional regulator of sporulation that is required for relapsing disease and transmission in mice. RESULTS: Here we describe a genome-wide approach using a combined transcriptomic and proteomic analysis to identify Spo0A regulated genes. Our results validate Spo0A as a positive regulator of putative and novel sporulation genes as well as components of the mature spore proteome. We also show that Spo0A regulates a number of virulence-associated factors such as flagella and metabolic pathways including glucose fermentation leading to butyrate production. CONCLUSIONS: The C. difficile spo0A gene is a global transcriptional regulator that controls diverse sporulation, virulence and metabolic phenotypes coordinating pathogen adaptation to a wide range of host interactions. Additionally, the rich breadth of functional data allowed us to significantly update the annotation of the C. difficile 630 reference genome which will facilitate basic and applied research on this emerging pathogen.
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- 2014
11. The agr Locus Regulates Virulence and Colonization Genes in Clostridium difficile 027
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Martin, MJ, Clare, S, Goulding, D, Faulds-Pain, A, Barquist, L, Browne, HP, Pettit, L, Dougan, G, Lawley, TD, Wren, BW, Martin, MJ, Clare, S, Goulding, D, Faulds-Pain, A, Barquist, L, Browne, HP, Pettit, L, Dougan, G, Lawley, TD, and Wren, BW
- Abstract
The transcriptional regulator AgrA, a member of the LytTR family of proteins, plays a key role in controlling gene expression in some Gram-positive pathogens, including Staphylococcus aureus and Enterococcus faecalis. AgrA is encoded by the agrACDB global regulatory locus, and orthologues are found within the genome of most Clostridium difficile isolates, including the epidemic lineage 027/BI/NAP1. Comparative RNA sequencing of the wild type and otherwise isogenic agrA null mutant derivatives of C. difficile R20291 revealed a network of approximately 75 differentially regulated transcripts at late exponential growth phase, including many genes associated with flagellar assembly and function, such as the major structural subunit, FliC. Other differentially regulated genes include several involved in bis-(3'-5')-cyclic dimeric GMP (c-di-GMP) synthesis and toxin A expression. C. difficile 027 R20291 agrA mutant derivatives were poorly flagellated and exhibited reduced levels of colonization and relapses in the murine infection model. Thus, the agr locus likely plays a contributory role in the fitness and virulence potential of C. difficile strains in the 027/BI/NAP1 lineage.
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- 2013
12. Emergence and global spread of epidemic healthcare-associated Clostridium difficile
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He, M, Miyajima, F, Roberts, P, Ellison, L, Pickard, DJ, Martin, MJ, Connor, TR, Harris, SR, Fairley, D, Bamford, KB, D'Arc, S, Brazier, J, Brown, D, Coia, JE, Douce, G, Gerding, D, Kim, HJ, Koh, TH, Kato, H, Senoh, M, Louie, T, Michell, S, Butt, E, Peacock, SJ, Brown, NM, Riley, T, Songer, G, Wilcox, M, Pirmohamed, M, Kuijper, E, Hawkey, P, Wren, BW, Dougan, G, Parkhill, J, Lawley, TD, He, M, Miyajima, F, Roberts, P, Ellison, L, Pickard, DJ, Martin, MJ, Connor, TR, Harris, SR, Fairley, D, Bamford, KB, D'Arc, S, Brazier, J, Brown, D, Coia, JE, Douce, G, Gerding, D, Kim, HJ, Koh, TH, Kato, H, Senoh, M, Louie, T, Michell, S, Butt, E, Peacock, SJ, Brown, NM, Riley, T, Songer, G, Wilcox, M, Pirmohamed, M, Kuijper, E, Hawkey, P, Wren, BW, Dougan, G, Parkhill, J, and Lawley, TD
- Abstract
Epidemic C. difficile (027/BI/NAP1) has rapidly emerged in the past decade as the leading cause of antibiotic-associated diarrhea worldwide. However, the key events in evolutionary history leading to its emergence and the subsequent patterns of global spread remain unknown. Here, we define the global population structure of C. difficile 027/BI/NAP1 using whole-genome sequencing and phylogenetic analysis. We show that two distinct epidemic lineages, FQR1 and FQR2, not one as previously thought, emerged in North America within a relatively short period after acquiring the same fluoroquinolone resistance-conferring mutation and a highly related conjugative transposon. The two epidemic lineages showed distinct patterns of global spread, and the FQR2 lineage spread more widely, leading to healthcare-associated outbreaks in the UK, continental Europe and Australia. Our analysis identifies key genetic changes linked to the rapid transcontinental dissemination of epidemic C. difficile 027/BI/NAP1 and highlights the routes by which it spreads through the global healthcare system.
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- 2013
13. Targeted Restoration of the Intestinal Microbiota with a Simple, Defined Bacteriotherapy Resolves Relapsing Clostridium difficile Disease in Mice
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Gilmore, MS, Lawley, TD, Clare, S, Walker, AW, Stares, MD, Connor, TR, Raisen, C, Goulding, D, Rad, R, Schreiber, F, Brandt, C, Deakin, LJ, Pickard, DJ, Duncan, SH, Flint, HJ, Clark, TG, Parkhill, J, Dougan, G, Gilmore, MS, Lawley, TD, Clare, S, Walker, AW, Stares, MD, Connor, TR, Raisen, C, Goulding, D, Rad, R, Schreiber, F, Brandt, C, Deakin, LJ, Pickard, DJ, Duncan, SH, Flint, HJ, Clark, TG, Parkhill, J, and Dougan, G
- Abstract
Relapsing C. difficile disease in humans is linked to a pathological imbalance within the intestinal microbiota, termed dysbiosis, which remains poorly understood. We show that mice infected with epidemic C. difficile (genotype 027/BI) develop highly contagious, chronic intestinal disease and persistent dysbiosis characterized by a distinct, simplified microbiota containing opportunistic pathogens and altered metabolite production. Chronic C. difficile 027/BI infection was refractory to vancomycin treatment leading to relapsing disease. In contrast, treatment of C. difficile 027/BI infected mice with feces from healthy mice rapidly restored a diverse, healthy microbiota and resolved C. difficile disease and contagiousness. We used this model to identify a simple mixture of six phylogenetically diverse intestinal bacteria, including novel species, which can re-establish a health-associated microbiota and clear C. difficile 027/BI infection from mice. Thus, targeting a dysbiotic microbiota with a defined mixture of phylogenetically diverse bacteria can trigger major shifts in the microbial community structure that displaces C. difficile and, as a result, resolves disease and contagiousness. Further, we demonstrate a rational approach to harness the therapeutic potential of health-associated microbial communities to treat C. difficile disease and potentially other forms of intestinal dysbiosis.
- Published
- 2012
14. Comparative Whole Genome Sequence Analysis of the Carcinogenic Bacterial Model Pathogen Helicobacter felis
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Arnold, IC, Zigova, Z, Holden, M, Lawley, TD, Rad, R, Dougan, G, Falkow, S, Bentley, SD, Mueller, A, Arnold, IC, Zigova, Z, Holden, M, Lawley, TD, Rad, R, Dougan, G, Falkow, S, Bentley, SD, and Mueller, A
- Abstract
The gram-negative bacterium Helicobacter felis naturally colonizes the gastric mucosa of dogs and cats. Due to its ability to persistently infect laboratory mice, H. felis has been used extensively to experimentally model gastric disorders induced in humans by H. pylori. We determined the 1.67 Mb genome sequence of H. felis using combined Solexa and 454 pyrosequencing, annotated the genome, and compared it with multiple previously published Helicobacter genomes. About 1,063 (63.6%) of the 1,671 genes identified in the H. felis genome have orthologues in H. pylori, its closest relative among the fully sequenced Helicobacter species. Many H. pylori virulence factors are shared by H. felis: these include the gamma-glutamyl transpeptidase GGT, the immunomodulator NapA, and the secreted enzymes collagenase and HtrA. Helicobacter felis lacks a Cag pathogenicity island and the vacuolating cytotoxin VacA but possesses a complete comB system conferring natural competence. Remarkable features of the H. felis genome include its paucity of transcriptional regulators and an extraordinary abundance of chemotaxis sensors and restriction/modification systems. Helicobacter felis possesses an episomally replicating 6.7-kb plasmid and harbors three chromosomal regions with deviating GC content. These putative horizontally acquired regions show homology and synteny with the recently isolated H. pylori plasmid pHPPC4 and homology to Campylobacter bacteriophage genes (transposases, structural, and lytic genes), respectively. In summary, the H. felis genome harbors a variety of putative mobile elements that are unique among Helicobacter species and may contribute to this pathogen's carcinogenic properties.
- Published
- 2011
15. Comparative genome and phenotypic analysis of Clostridium difficile 027 strains provides insight into the evolution of a hypervirulent bacterium
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Stabler, RA, He, M, Dawson, L, Martin, M, Valiente, E, Corton, C, Lawley, TD, Sebaihia, M, Quail, MA, Rose, G, Gerding, DN, Gibert, M, Popoff, MR, Parkhill, J, Dougan, G, Wren, BW, Stabler, RA, He, M, Dawson, L, Martin, M, Valiente, E, Corton, C, Lawley, TD, Sebaihia, M, Quail, MA, Rose, G, Gerding, DN, Gibert, M, Popoff, MR, Parkhill, J, Dougan, G, and Wren, BW
- Abstract
BACKGROUND: The continued rise of Clostridium difficile infections worldwide has been accompanied by the rapid emergence of a highly virulent clone designated PCR-ribotype 027. To understand more about the evolution of this virulent clone, we made a three-way genomic and phenotypic comparison of an 'historic' non-epidemic 027 C. difficile (CD196), a recent epidemic and hypervirulent 027 (R20291) and a previously sequenced PCR-ribotype 012 strain (630). RESULTS: Although the genomes are highly conserved, the 027 genomes have 234 additional genes compared to 630, which may contribute to the distinct phenotypic differences we observe between these strains relating to motility, antibiotic resistance and toxicity. The epidemic 027 strain has five unique genetic regions, absent from both the non-epidemic 027 and strain 630, which include a novel phage island, a two component regulatory system and transcriptional regulators. CONCLUSIONS: A comparison of a series of 027 isolates showed that some of these genes appeared to have been gained by 027 strains over the past two decades. This study provides genetic markers for the identification of 027 strains and offers a unique opportunity to explain the recent emergence of a hypervirulent bacterium.
- Published
- 2009
16. Gut Microbiome in Human Melioidosis: Composition and Resistome Dynamics from Diagnosis to Discovery.
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Chowdhury S, Kullberg RFJ, Haak BW, Duran C, Earny VA, Eshwara VK, Lawley TD, Wiersinga WJ, and Mukhopadhyay C
- Abstract
Background: Melioidosis, attributable to the soil-dwelling bacterium Burkholderia pseudomallei , stands as a paramount global health challenge, necessitating extended courses of antibiotics. While murine studies identified the gut microbiota as a modulator of bacterial dissemination during melioidosis, the human intestinal microbiota during melioidosis remains uncharacterized. Here, we characterized gut microbiota composition and antimicrobial resistance (AMR) genes at diagnosis, during treatment, and postdischarge for melioidosis. We hypothesized that the gut microbiota of melioidosis patients would be extensively distorted., Methods: In this prospective observational cohort, stool samples of patients with culture-confirmed melioidosis admitted to a tertiary care hospital in India were collected at diagnosis, 14 days after diagnosis, or discharge (whichever occurred first) and at 6 months postinfection. Family members or neighbors served as community controls. The gut microbiota and resistome were profiled by shotgun metagenomic sequencing., Results: We longitudinally analyzed the gut microbiota of 70 fecal samples from 28 patients and 16 community controls. At diagnosis, the gut microbiota of patients differed from that of controls, characterized by high abundances of potentially pathogenic bacteria, a loss of butyrate-producing bacteria, and higher levels of AMR genes. Microbiota composition and resistome remained different from community controls at 6 months, driven by total antibiotic exposure. During hospitalization, gut microbiota profiles were associated with secondary Klebsiella pneumoniae infections., Conclusions: This first study on gut microbiota composition and resistome in human melioidosis showed extensive disruptions during hospitalization, with limited signs of restoration 6 months postinfection. Given the adverse outcomes linked with microbiome perturbations, limiting microbiota disruptions or using microbiota-restorative therapies (eg, butyrate-producing probiotics) may be beneficial., Competing Interests: Potential conflicts of interest. The authors declare no potential conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)
- Published
- 2024
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17. Examining the healthy human microbiome concept.
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Joos R, Boucher K, Lavelle A, Arumugam M, Blaser MJ, Claesson MJ, Clarke G, Cotter PD, De Sordi L, Dominguez-Bello MG, Dutilh BE, Ehrlich SD, Ghosh TS, Hill C, Junot C, Lahti L, Lawley TD, Licht TR, Maguin E, Makhalanyane TP, Marchesi JR, Matthijnssens J, Raes J, Ravel J, Salonen A, Scanlan PD, Shkoporov A, Stanton C, Thiele I, Tolstoy I, Walter J, Yang B, Yutin N, Zhernakova A, Zwart H, Doré J, and Ross RP
- Abstract
Human microbiomes are essential to health throughout the lifespan and are increasingly recognized and studied for their roles in metabolic, immunological and neurological processes. Although the full complexity of these microbial communities is not fully understood, their clinical and industrial exploitation is well advanced and expanding, needing greater oversight guided by a consensus from the research community. One of the most controversial issues in microbiome research is the definition of a 'healthy' human microbiome. This concept is complicated by the microbial variability over different spatial and temporal scales along with the challenge of applying a unified definition to the spectrum of healthy microbiome configurations. In this Perspective, we examine the progress made and the key gaps that remain to be addressed to fully harness the benefits of the human microbiome. We propose a road map to expand our knowledge of the microbiome-health relationship, incorporating epidemiological approaches informed by the unique ecological characteristics of these communities., (© 2024. Springer Nature Limited.)
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- 2024
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18. Primary succession of Bifidobacteria drives pathogen resistance in neonatal microbiota assembly.
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Shao Y, Garcia-Mauriño C, Clare S, Dawson NJR, Mu A, Adoum A, Harcourt K, Liu J, Browne HP, Stares MD, Rodger A, Brocklehurst P, Field N, and Lawley TD
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- Humans, Animals, Infant, Newborn, Mice, Female, United Kingdom, Metagenomics, Enterococcus faecalis genetics, Enterococcus faecalis isolation & purification, Milk, Human microbiology, Male, Feces microbiology, Gastrointestinal Microbiome, Bifidobacterium genetics, Bifidobacterium isolation & purification
- Abstract
Human microbiota assembly commences at birth, seeded by both maternal and environmental microorganisms. Ecological theory postulates that primary colonizers dictate microbial community assembly outcomes, yet such microbial priority effects in the human gut remain underexplored. Here using longitudinal faecal metagenomics, we characterized neonatal microbiota assembly for a cohort of 1,288 neonates from the UK. We show that the pioneering neonatal gut microbiota can be stratified into one of three distinct community states, each dominated by a single microbial species and influenced by clinical and host factors, such as maternal age, ethnicity and parity. A community state dominated by Enterococcus faecalis displayed stochastic microbiota assembly with persistent high pathogen loads into infancy. In contrast, community states dominated by Bifidobacterium, specifically B. longum and particularly B. breve, exhibited a stable assembly trajectory and long-term pathogen colonization resistance, probably due to strain-specific functional adaptions to a breast milk-rich neonatal diet. Consistent with our human cohort observation, B. breve demonstrated priority effects and conferred pathogen colonization resistance in a germ-free mouse model. Our findings solidify the crucial role of Bifidobacteria as primary colonizers in shaping the microbiota assembly and functions in early life., (© 2024. The Author(s).)
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- 2024
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19. Gut microbiota and immune profiling of microbiota-humanised versus wildtype mouse models of hepatointestinal schistosomiasis.
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Stark KA, Rinaldi G, Costain A, Clare S, Tolley C, Almeida A, McCarthy C, Harcourt K, Brandt C, Lawley TD, Berriman M, MacDonald AS, Forde-Thomas JE, Hulme BJ, Hoffmann KF, Cantacessi C, and Cortés A
- Abstract
Mounting evidence of the occurrence of direct and indirect interactions between the human blood fluke, Schistosoma mansoni, and the gut microbiota of rodent models raises questions on the potential role(s) of the latter in the pathophysiology of hepatointestinal schistosomiasis. However, substantial differences in both the composition and function between the gut microbiota of laboratory rodents and that of humans hinders an in-depth understanding of the significance of such interactions for human schistosomiasis. Taking advantage of the availability of a human microbiota-associated mouse model (HMA), we have previously highlighted differences in infection-associated changes in gut microbiota composition between HMA and wildtype (WT) mice. To further explore the dynamics of schistosome-microbiota relationships in HMA mice, in this study we (i) characterize qualitative and quantitative changes in gut microbiota composition of a distinct line of HMA mice (D2 HMA) infected with S. mansoni prior to and following the onset of parasite egg production; (ii) profile local and systemic immune responses against the parasite in HMA as well as WT mice and (iii) assess levels of faecal inflammatory markers and occult blood as indirect measures of gut tissue damage. We show that patent S. mansoni infection is associated with reduced bacterial alpha diversity in the gut of D2 HMA mice, alongside expansion of hydrogen sulphide-producing bacteria. Similar systemic humoral responses against S. mansoni in WT and D2 HMA mice, as well as levels of faecal lipocalin and markers of alternatively activated macrophages, suggest that these are independent of baseline gut microbiota composition. Qualitative comparative analyses between faecal microbial profiles of S. mansoni-infected WT and distinct lines of HMA mice reveal that, while infection-induced alterations of the gut microbiota composition are highly dependent on the baseline flora, bile acid composition and metabolism may represent key elements of schistosome-microbiota interactions through the gut-liver axis., (© 2024. The Author(s).)
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- 2024
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20. A gut microbial signature for combination immune checkpoint blockade across cancer types.
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Gunjur A, Shao Y, Rozday T, Klein O, Mu A, Haak BW, Markman B, Kee D, Carlino MS, Underhill C, Frentzas S, Michael M, Gao B, Palmer J, Cebon J, Behren A, Adams DJ, and Lawley TD
- Subjects
- Humans, Immune Checkpoint Inhibitors therapeutic use, Gastrointestinal Microbiome genetics, Neoplasms drug therapy, Neoplasms genetics
- Abstract
Immune checkpoint blockade (ICB) targeting programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte protein 4 (CTLA-4) can induce remarkable, yet unpredictable, responses across a variety of cancers. Studies suggest that there is a relationship between a cancer patient's gut microbiota composition and clinical response to ICB; however, defining microbiome-based biomarkers that generalize across cohorts has been challenging. This may relate to previous efforts quantifying microbiota to species (or higher taxonomic rank) abundances, whereas microbial functions are often strain specific. Here, we performed deep shotgun metagenomic sequencing of baseline fecal samples from a unique, richly annotated phase 2 trial cohort of patients with diverse rare cancers treated with combination ICB (n = 106 discovery cohort). We demonstrate that strain-resolved microbial abundances improve machine learning predictions of ICB response and 12-month progression-free survival relative to models built using species-rank quantifications or comprehensive pretreatment clinical factors. Through a meta-analysis of gut metagenomes from a further six comparable studies (n = 364 validation cohort), we found cross-cancer (and cross-country) validity of strain-response signatures, but only when the training and test cohorts used concordant ICB regimens (anti-PD-1 monotherapy or combination anti-PD-1 plus anti-CTLA-4). This suggests that future development of gut microbiome diagnostics or therapeutics should be tailored according to ICB treatment regimen rather than according to cancer type., (© 2024. The Author(s).)
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- 2024
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21. Genomic attributes of airway commensal bacteria and mucosa.
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Cuthbertson L, Löber U, Ish-Horowicz JS, McBrien CN, Churchward C, Parker JC, Olanipekun MT, Burke C, McGowan A, Davies GA, Lewis KE, Hopkin JM, Chung KF, O'Carroll O, Faul J, Creaser-Thomas J, Andrews M, Ghosal R, Piatek S, Willis-Owen SAG, Bartolomaeus TUP, Birkner T, Dwyer S, Kumar N, Turek EM, William Musk A, Hui J, Hunter M, James A, Dumas ME, Filippi S, Cox MJ, Lawley TD, Forslund SK, Moffatt MF, and Cookson WOC
- Subjects
- Humans, Symbiosis, Immunity, Mucosal, Genomics, Mucous Membrane microbiology, Bacteria genetics
- Abstract
Microbial communities at the airway mucosal barrier are conserved and highly ordered, in likelihood reflecting co-evolution with human host factors. Freed of selection to digest nutrients, the airway microbiome underpins cognate management of mucosal immunity and pathogen resistance. We show here the initial results of systematic culture and whole-genome sequencing of the thoracic airway bacteria, identifying 52 novel species amongst 126 organisms that constitute 75% of commensals typically present in heathy individuals. Clinically relevant genes encode antimicrobial synthesis, adhesion and biofilm formation, immune modulation, iron utilisation, nitrous oxide (NO) metabolism and sphingolipid signalling. Using whole-genome content we identify dysbiotic features that may influence asthma and chronic obstructive pulmonary disease. We match isolate gene content to transcripts and metabolites expressed late in airway epithelial differentiation, identifying pathways to sustain host interactions with microbiota. Our results provide a systematic basis for decrypting interactions between commensals, pathogens, and mucosa in lung diseases of global significance., (© 2024. The Author(s).)
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- 2024
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22. Boosting microbiome science worldwide could save millions of children's lives.
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Browne HP, Iqbal NT, Osman M, Tigoi C, Lawley TD, Gordon JI, Ahmed T, and Kariuki S
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- Child, Humans, Global Health trends, Microbiota, Biomedical Research trends, Internationality, Child Health trends
- Published
- 2024
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23. Screening for Clostridioides difficile colonization at admission to the hospital: a multi-centre study.
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Crobach MJT, Hornung BVH, Verduin C, Vos MC, Hopman J, Kumar N, Harmanus C, Sanders I, Terveer EM, Stares MD, Lawley TD, and Kuijper EJ
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- Humans, Clostridioides genetics, Multilocus Sequence Typing, Hospitalization, Hospitals, Ribotyping, Clostridioides difficile genetics, Clostridium Infections diagnosis, Clostridium Infections epidemiology, Clostridium Infections microbiology
- Abstract
Objectives: To assess the value of screening for Clostridioides difficile colonization (CDC) at hospital admission in an endemic setting., Methods: A multi-centre study was conducted at four hospitals located across the Netherlands. Newly admitted patients were screened for CDC. The risk of development of Clostridioides difficile infection (CDI) during admission and 1-year follow-up was assessed in patients with and without colonization. C. difficile isolates from patients with colonization were compared with isolates from incident CDI cases using core genome multi-locus sequence typing to determine whether onwards transmission had occurred., Results: CDC was present in 108 of 2211 admissions (4.9%), whereas colonization with a toxigenic strain (toxigenic Clostridoides difficile colonization [tCDC]) was present in 68 of 2211 admissions (3.1%). Among these 108 patients with colonization, diverse PCR ribotypes were found and no 'hypervirulent' PCR ribotype 027 (RT027) was detected (95% CI, 0-0.028). None of the patients with colonization developed CDI during admission (0/49; 95% CI, 0-0.073) or 1-year follow-up (0/38; 95% CI, 0-0.93). Core genome multi-locus sequence typing identified six clusters with genetically related isolates from patients with tCDC and CDI; however, in these clusters, only one possible transmission event from a patient with tCDC to a patient with CDI was identified based on epidemiological data., Conclusion: In this endemic setting with a low prevalence of 'hypervirulent' strains, screening for CDC at admission did not detect any patients with CDC who progressed to symptomatic CDI and detected only one possible transmission event from a patient with colonization to a patient with CDI. Thus, screening for CDC at admission is not useful in this setting., Competing Interests: Transparency declaration The authors declare that they have no conflicts of interest. This work was supported by the Netherlands Organisation for Health Research and Development, ZonMW (grant 50-52200-98-035) and Wellcome Sanger core funding (WT098051)., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)
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- 2023
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24. Multi-level analysis of the gut-brain axis shows autism spectrum disorder-associated molecular and microbial profiles.
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Morton JT, Jin DM, Mills RH, Shao Y, Rahman G, McDonald D, Zhu Q, Balaban M, Jiang Y, Cantrell K, Gonzalez A, Carmel J, Frankiensztajn LM, Martin-Brevet S, Berding K, Needham BD, Zurita MF, David M, Averina OV, Kovtun AS, Noto A, Mussap M, Wang M, Frank DN, Li E, Zhou W, Fanos V, Danilenko VN, Wall DP, Cárdenas P, Baldeón ME, Jacquemont S, Koren O, Elliott E, Xavier RJ, Mazmanian SK, Knight R, Gilbert JA, Donovan SM, Lawley TD, Carpenter B, Bonneau R, and Taroncher-Oldenburg G
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- Humans, Brain-Gut Axis, Cross-Sectional Studies, Bayes Theorem, Reproducibility of Results, Cytokines, Gastrointestinal Microbiome genetics, Autism Spectrum Disorder genetics, Autism Spectrum Disorder metabolism
- Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by heterogeneous cognitive, behavioral and communication impairments. Disruption of the gut-brain axis (GBA) has been implicated in ASD although with limited reproducibility across studies. In this study, we developed a Bayesian differential ranking algorithm to identify ASD-associated molecular and taxa profiles across 10 cross-sectional microbiome datasets and 15 other datasets, including dietary patterns, metabolomics, cytokine profiles and human brain gene expression profiles. We found a functional architecture along the GBA that correlates with heterogeneity of ASD phenotypes, and it is characterized by ASD-associated amino acid, carbohydrate and lipid profiles predominantly encoded by microbial species in the genera Prevotella, Bifidobacterium, Desulfovibrio and Bacteroides and correlates with brain gene expression changes, restrictive dietary patterns and pro-inflammatory cytokine profiles. The functional architecture revealed in age-matched and sex-matched cohorts is not present in sibling-matched cohorts. We also show a strong association between temporal changes in microbiome composition and ASD phenotypes. In summary, we propose a framework to leverage multi-omic datasets from well-defined cohorts and investigate how the GBA influences ASD., (© 2023. The Author(s).)
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- 2023
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25. Bacteriophage discovery to advance biotechnology and biotherapeutics.
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Mu A and Lawley TD
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- Biotechnology, Bacteriophages genetics
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- 2023
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26. Intelectin-1 binds and alters the localization of the mucus barrier-modifying bacterium Akkermansia muciniphila.
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Matute JD, Duan J, Flak MB, Griebel P, Tascon-Arcila JA, Doms S, Hanley T, Antanaviciute A, Gundrum J, Mark Welch JL, Sit B, Abtahi S, Fuhler GM, Grootjans J, Tran F, Stengel ST, White JR, Krupka N, Haller D, Clare S, Lawley TD, Kaser A, Simmons A, Glickman JN, Bry L, Rosenstiel P, Borisy G, Waldor MK, Baines JF, Turner JR, and Blumberg RS
- Subjects
- Humans, Mice, Animals, Mucus metabolism, Lectins, Verrucomicrobia metabolism, Colitis, Ulcerative metabolism, Colitis, Ulcerative microbiology, Colitis, Ulcerative pathology
- Abstract
Intelectin-1 (ITLN1) is a lectin secreted by intestinal epithelial cells (IECs) and upregulated in human ulcerative colitis (UC). We investigated how ITLN1 production is regulated in IECs and the biological effects of ITLN1 at the host-microbiota interface using mouse models. Our data show that ITLN1 upregulation in IECs from UC patients is a consequence of activating the unfolded protein response. Analysis of microbes coated by ITLN1 in vivo revealed a restricted subset of microorganisms, including the mucolytic bacterium Akkermansia muciniphila. Mice overexpressing intestinal ITLN1 exhibited decreased inner colonic mucus layer thickness and closer apposition of A. muciniphila to the epithelial cell surface, similar to alterations reported in UC. The changes in the inner mucus layer were microbiota and A. muciniphila dependent and associated with enhanced sensitivity to chemically induced and T cell-mediated colitis. We conclude that by determining the localization of a select group of bacteria to the mucus layer, ITLN1 modifies this critical barrier. Together, these findings may explain the impact of ITLN1 dysregulation on UC pathogenesis., (© 2022 Matute et al.)
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- 2023
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27. The heightened importance of the microbiome in cancer immunotherapy.
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Villemin C, Six A, Neville BA, Lawley TD, Robinson MJ, and Bakdash G
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- Humans, Immunotherapy, Bacteria, Microbiota, Neoplasms therapy, Neoplasms microbiology
- Abstract
The human microbiome is recognized as a key factor in health and disease. This has been further corroborated by identifying changes in microbiome composition and function as a novel hallmark in cancer. These effects are exerted through microbiome interactions with host cells, impacting a wide variety of developmental and physiological processes. In this review, we discuss some of the latest findings on how the bacterial component of the microbiome can influence outcomes for different cancer immunotherapy modalities, highlighting identified mechanisms of action. We also address the clinical efforts to utilize this knowledge to achieve better responses to immunotherapy. A refined understanding of microbiome variations in patients and microbiome-host interactions with cancer therapies is essential to realize optimal clinical responses., Competing Interests: Declaration of interests The authors declare no conflicts of interest., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2023
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28. Questioning the fetal microbiome illustrates pitfalls of low-biomass microbial studies.
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Kennedy KM, de Goffau MC, Perez-Muñoz ME, Arrieta MC, Bäckhed F, Bork P, Braun T, Bushman FD, Dore J, de Vos WM, Earl AM, Eisen JA, Elovitz MA, Ganal-Vonarburg SC, Gänzle MG, Garrett WS, Hall LJ, Hornef MW, Huttenhower C, Konnikova L, Lebeer S, Macpherson AJ, Massey RC, McHardy AC, Koren O, Lawley TD, Ley RE, O'Mahony L, O'Toole PW, Pamer EG, Parkhill J, Raes J, Rattei T, Salonen A, Segal E, Segata N, Shanahan F, Sloboda DM, Smith GCS, Sokol H, Spector TD, Surette MG, Tannock GW, Walker AW, Yassour M, and Walter J
- Subjects
- Animals, Female, Humans, Pregnancy, Amniotic Fluid immunology, Amniotic Fluid microbiology, Mammals, Placenta immunology, Placenta microbiology, Reproducibility of Results, Biomass, Microbiota genetics, Fetus immunology, Fetus microbiology, DNA Contamination
- Abstract
Whether the human fetus and the prenatal intrauterine environment (amniotic fluid and placenta) are stably colonized by microbial communities in a healthy pregnancy remains a subject of debate. Here we evaluate recent studies that characterized microbial populations in human fetuses from the perspectives of reproductive biology, microbial ecology, bioinformatics, immunology, clinical microbiology and gnotobiology, and assess possible mechanisms by which the fetus might interact with microorganisms. Our analysis indicates that the detected microbial signals are likely the result of contamination during the clinical procedures to obtain fetal samples or during DNA extraction and DNA sequencing. Furthermore, the existence of live and replicating microbial populations in healthy fetal tissues is not compatible with fundamental concepts of immunology, clinical microbiology and the derivation of germ-free mammals. These conclusions are important to our understanding of human immune development and illustrate common pitfalls in the microbial analyses of many other low-biomass environments. The pursuit of a fetal microbiome serves as a cautionary example of the challenges of sequence-based microbiome studies when biomass is low or absent, and emphasizes the need for a trans-disciplinary approach that goes beyond contamination controls by also incorporating biological, ecological and mechanistic concepts., (© 2023. Springer Nature Limited.)
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- 2023
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29. Strong pathogen competition in neonatal gut colonisation.
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Mäklin T, Thorpe HA, Pöntinen AK, Gladstone RA, Shao Y, Pesonen M, McNally A, Johnsen PJ, Samuelsen Ø, Lawley TD, Honkela A, and Corander J
- Subjects
- Female, Pregnancy, Infant, Newborn, Humans, Klebsiella, Metagenomics, Parturition, Escherichia coli genetics, Cesarean Section, Ecosystem
- Abstract
Opportunistic bacterial pathogen species and their strains that colonise the human gut are generally understood to compete against both each other and the commensal species colonising this ecosystem. Currently we are lacking a population-wide quantification of strain-level colonisation dynamics and the relationship of colonisation potential to prevalence in disease, and how ecological factors might be modulating these. Here, using a combination of latest high-resolution metagenomics and strain-level genomic epidemiology methods we performed a characterisation of the competition and colonisation dynamics for a longitudinal cohort of neonatal gut microbiomes. We found strong inter- and intra-species competition dynamics in the gut colonisation process, but also a number of synergistic relationships among several species belonging to genus Klebsiella, which includes the prominent human pathogen Klebsiella pneumoniae. No evidence of preferential colonisation by hospital-adapted pathogen lineages in either vaginal or caesarean section birth groups was detected. Our analysis further enabled unbiased assessment of strain-level colonisation potential of extra-intestinal pathogenic Escherichia coli (ExPEC) in comparison with their propensity to cause bloodstream infections. Our study highlights the importance of systematic surveillance of bacterial gut pathogens, not only from disease but also from carriage state, to better inform therapies and preventive medicine in the future., (© 2022. The Author(s).)
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- 2022
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30. The Childhood Acute Illness and Nutrition (CHAIN) network nested case-cohort study protocol: a multi-omics approach to understanding mortality among children in sub-Saharan Africa and South Asia.
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Njunge JM, Tickell K, Diallo AH, Sayeem Bin Shahid ASM, Gazi MA, Saleem A, Kazi Z, Ali S, Tigoi C, Mupere E, Lancioni CL, Yoshioka E, Chisti MJ, Mburu M, Ngari M, Ngao N, Gichuki B, Omer E, Gumbi W, Singa B, Bandsma R, Ahmed T, Voskuijl W, Williams TN, Macharia A, Makale J, Mitchel A, Williams J, Gogain J, Janjic N, Mandal R, Wishart DS, Wu H, Xia L, Routledge M, Gong YY, Espinosa C, Aghaeepour N, Liu J, Houpt E, Lawley TD, Browne H, Shao Y, Rwigi D, Kariuki K, Kaburu T, Uhlig HH, Gartner L, Jones K, Koulman A, Walson J, and Berkley J
- Abstract
Introduction : Many acutely ill children in low- and middle-income settings have a high risk of mortality both during and after hospitalisation despite guideline-based care. Understanding the biological mechanisms underpinning mortality may suggest optimal pathways to target for interventions to further reduce mortality. The Childhood Acute Illness and Nutrition (CHAIN) Network ( www.chainnnetwork.org) Nested Case-Cohort Study (CNCC) aims to investigate biological mechanisms leading to inpatient and post-discharge mortality through an integrated multi-omic approach. Methods and analysis ; The CNCC comprises a subset of participants from the CHAIN cohort (1278/3101 hospitalised participants, including 350 children who died and 658 survivors, and 270/1140 well community children of similar age and household location) from nine sites in six countries across sub-Saharan Africa and South Asia. Systemic proteome, metabolome, lipidome, lipopolysaccharides, haemoglobin variants, toxins, pathogens, intestinal microbiome and biomarkers of enteropathy will be determined. Computational systems biology analysis will include machine learning and multivariate predictive modelling with stacked generalization approaches accounting for the different characteristics of each biological modality. This systems approach is anticipated to yield mechanistic insights, show interactions and behaviours of the components of biological entities, and help develop interventions to reduce mortality among acutely ill children. Ethics and dissemination . The CHAIN Network cohort and CNCC was approved by institutional review boards of all partner sites. Results will be published in open access, peer reviewed scientific journals and presented to academic and policy stakeholders. Data will be made publicly available, including uploading to recognised omics databases. Trial registration NCT03208725., Competing Interests: No competing interests were disclosed., (Copyright: © 2022 Njunge JM et al.)
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- 2022
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31. The association between early-life gut microbiota and childhood respiratory diseases: a systematic review.
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Alcazar CG, Paes VM, Shao Y, Oesser C, Miltz A, Lawley TD, Brocklehurst P, Rodger A, and Field N
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- Infant, Humans, Infant, Newborn, Child, Preschool, Child, Adolescent, RNA, Ribosomal, 16S genetics, Feces microbiology, Bacteria genetics, Gastrointestinal Microbiome genetics, Asthma epidemiology, Respiration Disorders complications, Respiratory Tract Infections epidemiology
- Abstract
Data from animal models suggest a role of early-life gut microbiota in lung immune development, and in establishing susceptibility to respiratory infections and asthma in humans. This systematic review summarises the association between infant (ages 0-12 months) gut microbiota composition measured by genomic sequencing, and childhood (ages 0-18 years) respiratory diseases (ie, respiratory infections, wheezing, or asthma). Overall, there was evidence that low α-diversity and relative abundance of particular gut-commensal bacteria genera (Bifidobacterium, Faecalibacterium, Ruminococcus, and Roseburia) are associated with childhood respiratory diseases. However, results were inconsistent and studies had important limitations, including insufficient characterisation of bacterial taxa to species level, heterogeneous outcome definitions, residual confounding, and small sample sizes. Large longitudinal studies with stool sampling during the first month of life and shotgun metagenomic approaches to improve bacterial and fungal taxa resolution are needed. Standardising follow-up times and respiratory disease definitions and optimising causal statistical approaches might identify targets for primary prevention of childhood respiratory diseases., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)
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- 2022
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32. The gut microbial metabolic capacity of microbiome-humanized vs. wild type rodents reveals a likely dual role of intestinal bacteria in hepato-intestinal schistosomiasis.
- Author
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Cortés A, Martin J, Rosa BA, Stark KA, Clare S, McCarthy C, Harcourt K, Brandt C, Tolley C, Lawley TD, Mitreva M, Berriman M, Rinaldi G, and Cantacessi C
- Subjects
- Mice, Animals, Rodentia, Bacteria, Schistosomiasis mansoni, Gastrointestinal Microbiome, Microbiota, Schistosomiasis
- Abstract
Increasing evidence shows that the host gut microbiota might be involved in the immunological cascade that culminates with the formation of tissue granulomas underlying the pathophysiology of hepato-intestinal schistosomiasis. In this study, we investigated the impact of Schistosoma mansoni infection on the gut microbial composition and functional potential of both wild type and microbiome-humanized mice. In spite of substantial differences in microbiome composition at baseline, selected pathways were consistently affected by parasite infection. The gut microbiomes of infected mice of both lines displayed, amongst other features, enhanced capacity for tryptophan and butyrate production, which might be linked to the activation of mechanisms aimed to prevent excessive injuries caused by migrating parasite eggs. Complementing data from previous studies, our findings suggest that the host gut microbiome might play a dual role in the pathophysiology of schistosomiasis, where intestinal bacteria may contribute to egg-associated pathology while, in turn, protect the host from uncontrolled tissue damage., Competing Interests: The authors declare that they have no competing interests
- Published
- 2022
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33. Mother-infant transmission of human microbiota.
- Author
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Browne HP, Shao Y, and Lawley TD
- Subjects
- Bacteria genetics, Bifidobacterium, Child, Disease Resistance, Feces microbiology, Female, Humans, Infant, Infant, Newborn, Mothers, Pregnancy, Cesarean Section, Microbiota physiology
- Abstract
Humans are colonised by a highly adapted microbiota with coevolved functions that promote human health, development and disease resistance. Acquisition and assembly of the microbiota start at birth and recent evidence suggests that it coincides with, and informs, immune system development and regulation in the rapidly growing infant. Several large-scale studies have identified Bifidobacterium and Bacteroides species maternally transmitted to infants, many of which are capable of colonising over the longer term. Disruption of maternal transmission by caesarean section and antibiotic exposure around birth is associated with a higher incidence of pathogen colonisation and immune-related disorders in children. In this review, we discuss key maternally transmitted bacterial species, their sources and their potential role in shaping immune development. Maternal transmission of gut bacteria provides a microbial 'starter kit' for infants which promotes healthy growth and disease resistance. Optimising and nurturing this under-appreciated form of kinship should be considered as a priority., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)
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- 2022
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34. Two microbiota subtypes identified in irritable bowel syndrome with distinct responses to the low FODMAP diet.
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Vervier K, Moss S, Kumar N, Adoum A, Barne M, Browne H, Kaser A, Kiely CJ, Neville BA, Powell N, Raine T, Stares MD, Zhu A, De La Revilla Negro J, Lawley TD, and Parkes M
- Subjects
- Diet, Diet, Carbohydrate-Restricted, Disaccharides metabolism, Fermentation, Humans, Monosaccharides, Oligosaccharides, Gastrointestinal Microbiome, Irritable Bowel Syndrome
- Abstract
Objective: Reducing FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) can be clinically beneficial in IBS but the mechanism is incompletely understood. We aimed to detect microbial signatures that might predict response to the low FODMAP diet and assess whether microbiota compositional and functional shifts could provide insights into its mode of action., Design: We used metagenomics to determine high-resolution taxonomic and functional profiles of the stool microbiota from IBS cases and household controls (n=56 pairs) on their usual diet. Clinical response and microbiota changes were studied in 41 pairs after 4 weeks on a low FODMAP diet., Results: Unsupervised analysis of baseline IBS cases pre-diet identified two distinct microbiota profiles, which we refer to as IBS
P (pathogenic-like) and IBSH (health-like) subtypes. IBSP microbiomes were enriched in Firmicutes and genes for amino acid and carbohydrate metabolism, but depleted in Bacteroidetes species. IBSH microbiomes were similar to controls. On the low FODMAP diet, IBSH and control microbiota were unaffected, but the IBSP signature shifted towards a health-associated microbiome with an increase in Bacteroidetes (p=0.009), a decrease in Firmicutes species (p=0.004) and normalisation of primary metabolic genes. The clinical response to the low FODMAP diet was greater in IBSP subjects compared with IBSH (p=0.02)., Conclusion: 50% of IBS cases manifested a 'pathogenic' gut microbial signature. This shifted towards the healthy profile on the low FODMAP diet; and IBSP cases showed an enhanced clinical responsiveness to the dietary therapy. The effectiveness of FODMAP reduction in IBSP may result from the alterations in gut microbiota and metabolites produced. Microbiota signatures could be useful as biomarkers to guide IBS treatment; and investigating IBSP species and metabolic pathways might yield insights regarding IBS pathogenic mechanisms., Competing Interests: Competing interests: TR has received research/educational grants and/or speaker/consultation fees from AbbVie, Arena, AstraZeneca, BMS, Celgene, Ferring, Galapagos, Gilead, GSK, LabGenius, Janssen, Mylan, MSD, Novartis, Pfizer, Sandoz, Takeda and UCB. SM has received research/educational grants and/or speaker/consultation fees from AbbVie. MP has received research/educational grants and/or speaker/consultation fees from Takeda, Gilead and Pfizer. TDL is the co-founder and CSO of Microbiotica., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)- Published
- 2022
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35. 'Know thyself' - host factors influencing cancer response to immune checkpoint inhibitors.
- Author
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Gunjur A, Manrique-Rincón AJ, Klein O, Behren A, Lawley TD, Welsh SJ, and Adams DJ
- Subjects
- Humans, Immunologic Factors therapeutic use, Immunotherapy, United Kingdom, Immune Checkpoint Inhibitors therapeutic use, Neoplasms therapy
- Abstract
Immune checkpoint inhibitors (ICIs) have revolutionised oncology and are now standard-of-care for the treatment of a wide variety of solid neoplasms. However, tumour responses remain unpredictable, experienced by only a minority of ICI recipients across malignancy types. Therefore, there is an urgent need for better predictive biomarkers to identify a priori the patients most likely to benefit from these therapies. Despite considerable efforts, only three such biomarkers are FDA-approved for clinical use, and all rely on the availability of tumour tissue for immunohistochemical staining or genomic assays. There is emerging evidence that host factors - for example, genetic, metabolic, and immune factors, as well as the composition of one's gut microbiota - influence the response of a patient's cancer to ICIs. Tantalisingly, some of these factors are modifiable, paving the way for co-therapies that may enhance the therapeutic index of these treatments. Herein, we review key host factors that are of potential biomarker value for response to ICI therapy, with a particular focus on the proposed mechanisms for these influences. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland., (© 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.)
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- 2022
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36. Should we modulate the neonatal microbiome and what should be the goal?
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van Best N, Dominguez-Bello MG, Hornef MW, Jašarević E, Korpela K, and Lawley TD
- Subjects
- Goals, Gastrointestinal Microbiome, Microbiota
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- 2022
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37. Identification of gut microbial species linked with disease variability in a widely used mouse model of colitis.
- Author
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Forster SC, Clare S, Beresford-Jones BS, Harcourt K, Notley G, Stares MD, Kumar N, Soderholm AT, Adoum A, Wong H, Morón B, Brandt C, Dougan G, Adams DJ, Maloy KJ, Pedicord VA, and Lawley TD
- Subjects
- Animals, Bacteroidetes, Disease Models, Animal, Mice, Colitis chemically induced, Colitis microbiology, Gastrointestinal Microbiome, Inflammatory Bowel Diseases microbiology
- Abstract
Experimental mouse models are central to basic biomedical research; however, variability exists across genetically identical mice and mouse facilities making comparisons difficult. Whether specific indigenous gut bacteria drive immunophenotypic variability in mouse models of human disease remains poorly understood. We performed a large-scale experiment using 579 genetically identical laboratory mice from a single animal facility, designed to identify the causes of disease variability in the widely used dextran sulphate sodium mouse model of inflammatory bowel disease. Commonly used treatment endpoint measures-weight loss and intestinal pathology-showed limited correlation and varied across mouse lineages. Analysis of the gut microbiome, coupled with machine learning and targeted anaerobic culturing, identified and isolated two previously undescribed species, Duncaniella muricolitica and Alistipes okayasuensis, and demonstrated that they exert dominant effects in the dextran sulphate sodium model leading to variable treatment endpoint measures. We show that the identified gut microbial species are common, but not ubiquitous, in mouse facilities around the world, and suggest that researchers monitor for these species to provide experimental design opportunities for improved mouse models of human intestinal diseases., (© 2022. The Author(s).)
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- 2022
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38. Strain-level characterization of broad host range mobile genetic elements transferring antibiotic resistance from the human microbiome.
- Author
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Forster SC, Liu J, Kumar N, Gulliver EL, Gould JA, Escobar-Zepeda A, Mkandawire T, Pike LJ, Shao Y, Stares MD, Browne HP, Neville BA, and Lawley TD
- Subjects
- Animals, Anti-Bacterial Agents pharmacology, Bacteria genetics, Drug Resistance, Microbial genetics, Genes, Bacterial, Humans, Interspersed Repetitive Sequences genetics, Host Specificity genetics, Microbiota genetics
- Abstract
Mobile genetic elements (MGEs) carrying antibiotic resistance genes (ARGs) disseminate ARGs when they mobilise into new bacterial hosts. The nature of such horizontal gene transfer (HGT) events between human gut commensals and pathogens remain poorly characterised. Here, we compare 1354 cultured commensal strains (540 species) to 45,403 pathogen strains (12 species) and find 64,188 MGE-mediated ARG transfer events between the two groups using established methods. Among the 5931 MGEs, we find 15 broad host range elements predicted to have crossed different bacterial phyla while also occurring in animal and environmental microbiomes. We experimentally demonstrate that predicted broad host range MGEs can mobilise from commensals Dorea longicatena and Hungatella hathewayi to pathogen Klebsiella oxytoca, crossing phyla simultaneously. Our work establishes the MGE-mediated ARG dissemination network between human gut commensals and pathogens and highlights broad host range MGEs as targets for future ARG dissemination management., (© 2022. The Author(s).)
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- 2022
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39. The MITRE trial protocol: a study to evaluate the microbiome as a biomarker of efficacy and toxicity in cancer patients receiving immune checkpoint inhibitor therapy.
- Author
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Thompson NA, Stewart GD, Welsh SJ, Doherty GJ, Robinson MJ, Neville BA, Vervier K, Harris SR, Adams DJ, Dalchau K, Bruce D, Demiris N, Lawley TD, and Corrie PG
- Subjects
- Antibodies, Viral analysis, Antigens, Viral analysis, Carcinoma, Non-Small-Cell Lung therapy, Disease Progression, Feces microbiology, Humans, Immune Checkpoint Inhibitors adverse effects, Kidney Neoplasms therapy, Lung Neoplasms therapy, Melanoma therapy, Progression-Free Survival, Prospective Studies, SARS-CoV-2 immunology, Skin Neoplasms therapy, Gastrointestinal Microbiome immunology, Immune Checkpoint Inhibitors therapeutic use, Microbial Consortia immunology, Neoplasms therapy
- Abstract
Background: The gut microbiome is implicated as a marker of response to immune checkpoint inhibitors (ICI) based on preclinical mouse models and preliminary observations in limited patient series. Furthermore, early studies suggest faecal microbial transfer may have therapeutic potential, converting ICI non-responders into responders. So far, identification of specific responsible bacterial taxa has been inconsistent, which limits future application. The MITRE study will explore and validate a microbiome signature in a larger scale prospective study across several different cancer types., Methods: Melanoma, renal cancer and non-small cell lung cancer patients who are planned to receive standard immune checkpoint inhibitors are being recruited to the MITRE study. Longitudinal stool samples are collected prior to treatment, then at 6 weeks, 3, 6 and 12 months during treatment, or at disease progression/recurrence (whichever is sooner), as well as after a severe (≥grade 3 CTCAE v5.0) immune-related adverse event. Additionally, whole blood, plasma, buffy coat, RNA and peripheral blood mononuclear cells (PBMCs) is collected at similar time points and will be used for exploratory analyses. Archival tumour tissue, tumour biopsies at progression/relapse, as well as any biopsies from body organs collected after a severe toxicity are collected. The primary outcome measure is the ability of the microbiome signature to predict 1 year progression-free survival (PFS) in patients with advanced disease. Secondary outcomes include microbiome correlations with toxicity and other efficacy end-points. Biosamples will be used to explore immunological and genomic correlates. A sub-study will evaluate both COVID-19 antigen and antibody associations with the microbiome., Discussion: There is an urgent need to identify biomarkers that are predictive of treatment response, resistance and toxicity to immunotherapy. The data generated from this study will both help inform patient selection for these drugs and provide information that may allow therapeutic manipulation of the microbiome to improve future patient outcomes., Trial Registration: NCT04107168 , ClinicalTrials.gov, registered 09/27/2019. Protocol V3.2 (16/04/2021)., (© 2022. The Author(s).)
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- 2022
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40. The Mouse Gastrointestinal Bacteria Catalogue enables translation between the mouse and human gut microbiotas via functional mapping.
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Beresford-Jones BS, Forster SC, Stares MD, Notley G, Viciani E, Browne HP, Boehmler DJ, Soderholm AT, Kumar N, Vervier K, Cross JR, Almeida A, Lawley TD, and Pedicord VA
- Subjects
- Animals, Bacteria genetics, Bacteria metabolism, Butyrates metabolism, Genome, Bacterial, Humans, Metagenome genetics, Mice, Models, Animal, Bacteria classification, Bacteria isolation & purification, Gastrointestinal Microbiome physiology
- Abstract
Human health and disease have increasingly been shown to be impacted by the gut microbiota, and mouse models are essential for investigating these effects. However, the compositions of human and mouse gut microbiotas are distinct, limiting translation of microbiota research between these hosts. To address this, we constructed the Mouse Gastrointestinal Bacteria Catalogue (MGBC), a repository of 26,640 high-quality mouse microbiota-derived bacterial genomes. This catalog enables species-level analyses for mapping functions of interest and identifying functionally equivalent taxa between the microbiotas of humans and mice. We have complemented this with a publicly deposited collection of 223 bacterial isolates, including 62 previously uncultured species, to facilitate experimental investigation of individual commensal bacteria functions in vitro and in vivo. Together, these resources provide the ability to identify and test functionally equivalent members of the host-specific gut microbiotas of humans and mice and support the informed use of mouse models in human microbiota research., Competing Interests: Declaration of interests T.D.L. is a founder and CSO of Microbiotica. The other authors declare no competinginterests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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41. A purine metabolic checkpoint that prevents autoimmunity and autoinflammation.
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Saveljeva S, Sewell GW, Ramshorn K, Cader MZ, West JA, Clare S, Haag LM, de Almeida Rodrigues RP, Unger LW, Iglesias-Romero AB, Holland LM, Bourges C, Md-Ibrahim MN, Jones JO, Blumberg RS, Lee JC, Kaneider NC, Lawley TD, Bradley A, Dougan G, and Kaser A
- Subjects
- CD8-Positive T-Lymphocytes, Dendritic Cells, Lymphocyte Activation, Autoimmunity, Purines metabolism
- Abstract
Still's disease, the paradigm of autoinflammation-cum-autoimmunity, predisposes for a cytokine storm with excessive T lymphocyte activation upon viral infection. Loss of function of the purine nucleoside enzyme FAMIN is the sole known cause for monogenic Still's disease. Here we discovered that a FAMIN-enabled purine metabolon in dendritic cells (DCs) restrains CD4
+ and CD8+ T cell priming. DCs with absent FAMIN activity prime for enhanced antigen-specific cytotoxicity, IFNγ secretion, and T cell expansion, resulting in excessive influenza A virus-specific responses. Enhanced priming is already manifest with hypomorphic FAMIN-I254V, for which ∼6% of mankind is homozygous. FAMIN controls membrane trafficking and restrains antigen presentation in an NADH/NAD+ -dependent manner by balancing flux through adenine-guanine nucleotide interconversion cycles. FAMIN additionally converts hypoxanthine into inosine, which DCs release to dampen T cell activation. Compromised FAMIN consequently enhances immunosurveillance of syngeneic tumors. FAMIN is a biochemical checkpoint that protects against excessive antiviral T cell responses, autoimmunity, and autoinflammation., Competing Interests: Declaration of interests The University of Cambridge has filed patent applications relating to this work. The authors declare no other competing financial interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2022
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42. Citrobacter amalonaticus Inhibits the Growth of Citrobacter rodentium in the Gut Lumen.
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Mullineaux-Sanders C, Carson D, Hopkins EGD, Glegola-Madejska I, Escobar-Zepeda A, Browne HP, Lawley TD, and Frankel G
- Subjects
- Animals, Citrobacter rodentium genetics, Citrobacter rodentium physiology, Female, Gastrointestinal Microbiome, Humans, Intestinal Mucosa microbiology, Mice, Mice, Inbred C3H, Mice, Inbred C57BL, Citrobacter physiology, Citrobacter rodentium growth & development, Colon microbiology, Enterobacteriaceae Infections microbiology
- Abstract
The gut microbiota plays a crucial role in susceptibility to enteric pathogens, including Citrobacter rodentium, a model extracellular mouse pathogen that colonizes the colonic mucosa. C. rodentium infection outcomes vary between mouse strains, with C57BL/6 and C3H/HeN mice clearing and succumbing to the infection, respectively. Kanamycin (Kan) treatment at the peak of C57BL/6 mouse infection with Kan-resistant C. rodentium resulted in relocalization of the pathogen from the colonic mucosa and cecum to solely the cecal luminal contents; cessation of the Kan treatment resulted in rapid clearance of the pathogen. We now show that in C3H/HeN mice, following Kan-induced displacement of C. rodentium to the cecum, the pathogen stably colonizes the cecal lumens of 65% of the mice in the absence of continued antibiotic treatment, a phenomenon that we term antibiotic-induced bacterial commensalization (AIBC). AIBC C. rodentium was well tolerated by the host, which showed few signs of inflammation; passaged AIBC C. rodentium robustly infected naive C3H/HeN mice, suggesting that the AIBC state is transient and did not select for genetically avirulent C. rodentium mutants. Following withdrawal of antibiotic treatment, 35% of C3H/HeN mice were able to prevent C. rodentium commensalization in the gut lumen. These mice presented a bloom of a commensal species, Citrobacter amalonaticus, which inhibited the growth of C. rodentium in vitro in a contact-dependent manner and the luminal growth of AIBC C. rodentium in vivo . Overall, our data suggest that commensal species can confer colonization resistance to closely related pathogenic species. IMPORTANCE Gut bacterial infections involve three-way interactions between virulence factors, the host immune responses, and the microbiome. While the microbiome erects colonization resistance barriers, pathogens employ virulence factors to overcome them. Treating mice infected with kanamycin-resistant Citrobacter rodentium with kanamycin caused displacement of the pathogen from the colonic mucosa to the cecal lumen. Following withdrawal of the kanamycin treatment, 65% of the mice were persistently colonized by C. rodentium, which seemed to downregulate virulence factor expression. In this model of luminal gut colonization, 35% of mice were refractory to stable C. rodentium colonization, suggesting that their microbiotas were able to confer colonization resistance. We identify a commensal bacterium of the Citrobacter genus, C. amalonaticus , which inhibits C. rodentium growth in vitro and in vivo . These results show that the line separating commensal and pathogenic lifestyles is thin and multifactorial and that commensals may play a major role in combating enteric infection.
- Published
- 2021
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43. Host adaptation in gut Firmicutes is associated with sporulation loss and altered transmission cycle.
- Author
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Browne HP, Almeida A, Kumar N, Vervier K, Adoum AT, Viciani E, Dawson NJR, Forster SC, Cormie C, Goulding D, and Lawley TD
- Subjects
- Anaerobiosis genetics, Biological Evolution, Firmicutes growth & development, Humans, Metagenome, Spores, Bacterial growth & development, Firmicutes genetics, Gastrointestinal Microbiome genetics, Genome, Bacterial, Host Adaptation genetics, Microbiota genetics, Spores, Bacterial genetics, Symbiosis genetics
- Abstract
Background: Human-to-human transmission of symbiotic, anaerobic bacteria is a fundamental evolutionary adaptation essential for membership of the human gut microbiota. However, despite its importance, the genomic and biological adaptations underpinning symbiont transmission remain poorly understood. The Firmicutes are a dominant phylum within the intestinal microbiota that are capable of producing resistant endospores that maintain viability within the environment and germinate within the intestine to facilitate transmission. However, the impact of host transmission on the evolutionary and adaptive processes within the intestinal microbiota remains unknown., Results: We analyze 1358 genomes of Firmicutes bacteria derived from host and environment-associated habitats. Characterization of genomes as spore-forming based on the presence of sporulation-predictive genes reveals multiple losses of sporulation in many distinct lineages. Loss of sporulation in gut Firmicutes is associated with features of host-adaptation such as genome reduction and specialized metabolic capabilities. Consistent with these data, analysis of 9966 gut metagenomes from adults around the world demonstrates that bacteria now incapable of sporulation are more abundant within individuals but less prevalent in the human population compared to spore-forming bacteria., Conclusions: Our results suggest host adaptation in gut Firmicutes is an evolutionary trade-off between transmission range and colonization abundance. We reveal host transmission as an underappreciated process that shapes the evolution, assembly, and functions of gut Firmicutes., (© 2021. The Author(s).)
- Published
- 2021
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44. A novel technique capable of taking 'protected' biopsies for reliable assessment of the distribution of microbiota along the colonic mucosa.
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Strobbe F, Bénard MV, Rossen NG, de Vos WM, Kumar N, Lawley TD, Zoetendal EG, Hugenholtz F, and Ponsioen CY
- Subjects
- Adult, Aged, Anemia, Iron-Deficiency, Biopsy instrumentation, Female, Gastrointestinal Microbiome genetics, Humans, Male, Middle Aged, RNA, Ribosomal, 16S, Specimen Handling methods, Biopsy methods, Colon microbiology, Gastrointestinal Microbiome physiology, Intestinal Mucosa microbiology
- Abstract
We evaluated a novel 'protected' biopsy method to reliably ascertain the spatial distribution of the mucosa-adherent colonic microbiota. Apart from minor differences at genus level, overall similarities along the colon were high between the various areas, irrespective of protected or unprotected sampling., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)
- Published
- 2021
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45. Automated analysis of genomic sequences facilitates high-throughput and comprehensive description of bacteria.
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Hitch TCA, Riedel T, Oren A, Overmann J, Lawley TD, and Clavel T
- Abstract
The study of microbial communities is hampered by the large fraction of still unknown bacteria. However, many of these species have been isolated, yet lack a validly published name or description. The validation of names for novel bacteria requires that the uniqueness of those taxa is demonstrated and their properties are described. The accepted format for this is the protologue, which can be time-consuming to create. Hence, many research fields in microbiology and biotechnology will greatly benefit from new approaches that reduce the workload and harmonise the generation of protologues.We have developed Protologger, a bioinformatic tool that automatically generates all the necessary readouts for writing a detailed protologue. By producing multiple taxonomic outputs, functional features and ecological analysis using the 16S rRNA gene and genome sequences from a single species, the time needed to gather the information for describing novel taxa is substantially reduced. The usefulness of Protologger was demonstrated by using three published isolate collections to describe 34 novel taxa, encompassing 17 novel species and 17 novel genera, including the automatic generation of ecologically and functionally relevant names. We also highlight the need to utilise multiple taxonomic delineation methods, as while inconsistencies between each method occur, a combined approach provides robust placement. Protologger is open source; all scripts and datasets are available, along with a webserver at www.protologger.de., (© 2021. The Author(s).)
- Published
- 2021
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46. Identification of bacteria-derived HLA-bound peptides in melanoma.
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Kalaora S, Nagler A, Nejman D, Alon M, Barbolin C, Barnea E, Ketelaars SLC, Cheng K, Vervier K, Shental N, Bussi Y, Rotkopf R, Levy R, Benedek G, Trabish S, Dadosh T, Levin-Zaidman S, Geller LT, Wang K, Greenberg P, Yagel G, Peri A, Fuks G, Bhardwaj N, Reuben A, Hermida L, Johnson SB, Galloway-Peña JR, Shropshire WC, Bernatchez C, Haymaker C, Arora R, Roitman L, Eilam R, Weinberger A, Lotan-Pompan M, Lotem M, Admon A, Levin Y, Lawley TD, Adams DJ, Levesque MP, Besser MJ, Schachter J, Golani O, Segal E, Geva-Zatorsky N, Ruppin E, Kvistborg P, Peterson SN, Wargo JA, Straussman R, and Samuels Y
- Subjects
- Antigen Presentation, Bacteria classification, Bacteria genetics, Cell Line, Tumor, Coculture Techniques, HLA Antigens analysis, Humans, Lymphocytes, Tumor-Infiltrating cytology, Lymphocytes, Tumor-Infiltrating immunology, Melanoma pathology, Neoplasm Metastasis immunology, Phylogeny, RNA, Ribosomal, 16S genetics, Antigens, Bacterial analysis, Antigens, Bacterial immunology, Bacteria immunology, HLA Antigens immunology, Melanoma immunology, Melanoma microbiology, Peptides analysis, Peptides immunology
- Abstract
A variety of species of bacteria are known to colonize human tumours
1-11 , proliferate within them and modulate immune function, which ultimately affects the survival of patients with cancer and their responses to treatment12-14 . However, it is not known whether antigens derived from intracellular bacteria are presented by the human leukocyte antigen class I and II (HLA-I and HLA-II, respectively) molecules of tumour cells, or whether such antigens elicit a tumour-infiltrating T cell immune response. Here we used 16S rRNA gene sequencing and HLA peptidomics to identify a peptide repertoire derived from intracellular bacteria that was presented on HLA-I and HLA-II molecules in melanoma tumours. Our analysis of 17 melanoma metastases (derived from 9 patients) revealed 248 and 35 unique HLA-I and HLA-II peptides, respectively, that were derived from 41 species of bacteria. We identified recurrent bacterial peptides in tumours from different patients, as well as in different tumours from the same patient. Our study reveals that peptides derived from intracellular bacteria can be presented by tumour cells and elicit immune reactivity, and thus provides insight into a mechanism by which bacteria influence activation of the immune system and responses to therapy.- Published
- 2021
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47. Massive expansion of human gut bacteriophage diversity.
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Camarillo-Guerrero LF, Almeida A, Rangel-Pineros G, Finn RD, and Lawley TD
- Subjects
- Databases, Nucleic Acid, Host Specificity, Humans, Phylogeography, Bacteriophages genetics, Biodiversity, Gastrointestinal Microbiome
- Abstract
Bacteriophages drive evolutionary change in bacterial communities by creating gene flow networks that fuel ecological adaptions. However, the extent of viral diversity and its prevalence in the human gut remains largely unknown. Here, we introduce the Gut Phage Database, a collection of ∼142,000 non-redundant viral genomes (>10 kb) obtained by mining a dataset of 28,060 globally distributed human gut metagenomes and 2,898 reference genomes of cultured gut bacteria. Host assignment revealed that viral diversity is highest in the Firmicutes phyla and that ∼36% of viral clusters (VCs) are not restricted to a single species, creating gene flow networks across phylogenetically distinct bacterial species. Epidemiological analysis uncovered 280 globally distributed VCs found in at least 5 continents and a highly prevalent phage clade with features reminiscent of p-crAssphage. This high-quality, large-scale catalog of phage genomes will improve future virome studies and enable ecological and evolutionary analysis of human gut bacteriophages., Competing Interests: Declaration of Interests T.D.L. is the co-founder and Chief Scientific Officer of Microbiotica Pty Ltd, (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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48. Pangenome analysis reveals genetic isolation in Campylobacter hyointestinalis subspecies adapted to different mammalian hosts.
- Author
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Costa D, Lévesque S, Kumar N, Fresia P, Ferrés I, Lawley TD, and Iraola G
- Subjects
- Animals, Swine, Adaptation, Physiological, Campylobacter hyointestinalis genetics, Campylobacter hyointestinalis isolation & purification, Campylobacter hyointestinalis pathogenicity, Genetic Variation, Genome, Bacterial, Phylogeny
- Abstract
Campylobacter hyointestinalis is an emerging pathogen currently divided in two subspecies: C. hyointestinalis subsp. lawsonii which is predominantly recovered from pigs, and C. hyointestinalis subsp. hyointestinalis which can be found in a much wider range of mammalian hosts. Despite C. hyointestinalis being reported as an emerging pathogen, its evolutionary and host-associated diversification patterns are still vastly unexplored. For this reason, we generated whole-genome sequences of 13 C. hyointestinalis subsp. hyointestinalis strains and performed a comprehensive comparative analysis including publicly available C. hyointestinalis subsp. hyointestinalis and C. hyointestinalis subsp. lawsonii genomes, to gain insight into the genomic variation of these differentially-adapted subspecies. Both subspecies are distinct phylogenetic lineages which present an apparent barrier to homologous recombination, suggesting genetic isolation. This is further supported by accessory gene patterns that recapitulate the core genome phylogeny. Additionally, C. hyointestinalis subsp. hyointestinalis presents a bigger and more diverse accessory genome, which probably reflects its capacity to colonize different mammalian hosts unlike C. hyointestinalis subsp. lawsonii that is presumably host-restricted. This greater plasticity in the accessory genome of C. hyointestinalis subsp. hyointestinalis correlates to a higher incidence of genome-wide recombination events, that may be the underlying mechanism driving its diversification. Concordantly, both subspecies present distinct patterns of gene families involved in genome plasticity and DNA repair like CRISPR-associated proteins and restriction-modification systems. Together, our results provide an overview of the genetic mechanisms shaping the genomes of C. hyointestinalis subspecies, contributing to understand the biology of Campylobacter species that are increasingly recognized as emerging pathogens.
- Published
- 2021
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49. Comprehensive genome analyses of Sellimonas intestinalis , a potential biomarker of homeostasis gut recovery.
- Author
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Muñoz M, Guerrero-Araya E, Cortés-Tapia C, Plaza-Garrido A, Lawley TD, and Paredes-Sabja D
- Subjects
- Bacterial Proteins genetics, Clostridiales genetics, Clostridiales isolation & purification, Feces microbiology, Gene Regulatory Networks, Healthy Volunteers, High-Throughput Nucleotide Sequencing, Humans, Phylogeny, RNA, Ribosomal, 16S genetics, Clostridiales classification, Drug Resistance, Bacterial, Whole Genome Sequencing methods
- Abstract
Sellimonas intestinalis is a Gram-positive and anaerobic bacterial species previously considered as uncultivable. Although little is known about this Lachnospiraceae family member, its increased abundance has been reported in patients who have recovered from intestinal homeostasis after dysbiosis events. In this context, the aim of the present study was to take advantage of a massive in vitro culture protocol that allowed the recovery of extremely oxygen-sensitive species from faecal samples, which led to isolation of S. intestinalis . Whole genome analyses of 11 S . intestinalis genomes revealed that this species has a highly conserved genome with 99.7 % 16S rRNA gene sequence similarity, average nucleotide polymorphism results >95, and 50.1 % of its coding potential being part of the core genome. Despite this, the variable portion of its genome was informative enough to reveal the existence of three lineages (lineage-I including isolates from Chile and France, lineage-II from South Korea and Finland, and lineage-III from China and one isolate from the USA) and evidence of some recombination signals. The identification of a cluster of orthologous groups revealed a high number of genes involved in metabolism, including amino acid and carbohydrate transport as well as energy production and conversion, which matches with the metabolic profile previously reported for microbiota from healthy individuals. Additionally, virulence factors and antimicrobial resistance genes were found (mainly in lineage-III), which could favour their survival during antibiotic-induced dysbiosis. These findings provide the basis of knowledge about the potential of S. intestinalis as a bioindicator of intestinal homeostasis recovery and contribute to advancing the characterization of gut microbiota members with beneficial potential.
- Published
- 2020
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50. Gut-educated IgA plasma cells defend the meningeal venous sinuses.
- Author
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Fitzpatrick Z, Frazer G, Ferro A, Clare S, Bouladoux N, Ferdinand J, Tuong ZK, Negro-Demontel ML, Kumar N, Suchanek O, Tajsic T, Harcourt K, Scott K, Bashford-Rogers R, Helmy A, Reich DS, Belkaid Y, Lawley TD, McGavern DB, and Clatworthy MR
- Subjects
- Aged, Aging immunology, Animals, Blood-Brain Barrier immunology, Female, Fungi immunology, Germ-Free Life, Humans, Intestines cytology, Intestines microbiology, Male, Meninges blood supply, Meninges cytology, Mice, Mice, Inbred C57BL, Plasma Cells cytology, Cranial Sinuses immunology, Gastrointestinal Microbiome immunology, Immunoglobulin A, Secretory immunology, Intestines immunology, Meninges immunology, Plasma Cells immunology
- Abstract
The central nervous system has historically been viewed as an immune-privileged site, but recent data have shown that the meninges-the membranes that surround the brain and spinal cord-contain a diverse population of immune cells
1 . So far, studies have focused on macrophages and T cells, but have not included a detailed analysis of meningeal humoral immunity. Here we show that, during homeostasis, the mouse and human meninges contain IgA-secreting plasma cells. These cells are positioned adjacent to dural venous sinuses: regions of slow blood flow with fenestrations that can potentially permit blood-borne pathogens to access the brain2 . Peri-sinus IgA plasma cells increased with age and following a breach of the intestinal barrier. Conversely, they were scarce in germ-free mice, but their presence was restored by gut re-colonization. B cell receptor sequencing confirmed that meningeal IgA+ cells originated in the intestine. Specific depletion of meningeal plasma cells or IgA deficiency resulted in reduced fungal entrapment in the peri-sinus region and increased spread into the brain following intravenous challenge, showing that meningeal IgA is essential for defending the central nervous system at this vulnerable venous barrier surface.- Published
- 2020
- Full Text
- View/download PDF
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